Definition of steroid hormone receptors/nuclear receptors as transcription factors and the functions of their various domains, and discoveries of new receptors and ligands that have changed the field.

Jan-Åke Gustafsson is a leading scientist within the field of steroid hormone receptors/nuclear receptors. Several of his achievements have lead to true paradigm shifts in the field and represent breakthrough discoveries. He was first to show that a nuclear receptor, the glucocorticoid receptor, is composed of three separate structural and functional domains, a ligand binding domain, a DNA binding domain and a third domain identified by Gustafsson and coworkers by its immunogenic properties. Furthermore, the Gustafsson lab was first to purify a nuclear receptor, the glucocorticoid receptor, to homogeneity and thereby to show that it represents a single molecular species rather than a complex of multiple smaller subunits. At the time, this was an especially important finding since the literature was muddled with misconcepts based on impure and/or partially proteolyzed receptor preparations. Also, access to homogeneous nuclear receptor made it possible for Gustafsson to demonstrate specific DNA binding of glucocorticoid receptor to a glucocorticoid sensitive gene, the murine mammary tumour virus. This theretofore impossible achievement spurred a new, mechanistic era in nuclear receptor research, since in follow-up studies, Gustafsson et al could show that the specific glucocorticoid binding sites also represent glucocorticoid response elements, able to confer hormone responsiveness onto nearby genes. It is essential to point out that all of the above, absolutely central discoveries were made prior to cloning of nuclear receptors.

Furthermore, Gustafsson et al cloned the first (partial) cDNA of a nuclear receptor, the glucocorticoid receptor; the unique probes making this possible were the poly- and monoclonal antibodies against the glucocorticoid receptor developed by the Gustafsson lab. Another important milestone was the structure determination of the DNA-binding domain of the glucocorticoid receptor, the first ever nuclear receptor structure to be solved. During the recent fifteen years, Gustafsson has continued to be responsible for paradigm shifts in the field of nuclear receptor research. It was Gustafsson who first identified physiological ligands for a so called “orphan receptor”, namely fatty acids for the peroxisome proliferator activated receptor (PPAR), thereby integrating fatty acids into molecular endocrinology. Furthermore, Gustafsson discovered OR-1, later renamed LXRβ, an oxysterol activated nuclear receptor of paramount significance in e g regulation of cholesterol homeostasis and brain development.

Finally, and most importantly, Gustafsson and colleagues made the completely unexpected discovery of estrogen receptor β, a second estrogen receptor which has turned out to have functions far outside reproductive physiology and to be a very promising target in pharmaceutical development of novel drugs.

Ö. Wrange and J.-Å. Gustafsson: Separation of the hormone- and DNA-binding sites of the hepatic glucocorticoid receptor by means of proteolysis. J. Biol. Chem. 253, 856-865, 1978. FIRST DEMONSTRATION OF DOMAIN STRUCTURE OF A NUCLEAR RECEPTOR

International/National/Regional

2015 - Benning Lecture, School of Medicine, Salt Lake City, Utah

2014 - The Schueler Distinguished Lecture in Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana

Peer Review Groups/Grant Study Sections

2007 - Member of the selection committee for The King Faisal International Prize in Science.

2005-2007 - Member of the International Academic Advisory Committee (IAAC), Hefei, Peoples’s Republic of China.

1995 - Member of the International Advisory Board of the WHO Center in Oulu.

Journal Service

Member, currently and/or previously, of the editorial board or similar position in Steroids, The Journal of Steroid Biochemistry and Molecular Biology, Molecular Endocrinology, Breast Cancer Research and Treatment, The Prostate, Anticancer Research, Japanese Journal of Cancer Research, Journal of Molecular Medicine, Molecular Pharmacology, Cell Metabolism, Experimental Biology and Medicine and the International Journal of Oncology.

Board Certification

Elected Councillor/Board Member of the Swedish Medical Research Council during the 1990s (for 6 years).

Member of the Research Board of the Swedish Cancer Society during the 1980s and 1990s (for 6 years).

Member of the Research Board of the Swedish Council for Planning and Coordination of Research during the 1980s and 1990s (for 6 years).

Has been member of the Faculty Board of the Karolinska Institutet and has regularly carried out various assignments for the President’s Office of the Karolinska Institutet.

Awards Committee Member, Endocrine Society, USA 2002-06.

Elected Member of Council (Board) of Endocrine Society, USA, 2007 – 2010

Career/Academic Appointments

1964 - Bachelor of Medicine, Karolinska Institutet, Stockholm

1971 - Associate Professor in Chemistry, Karolinska Institutet

1976 - Professor of Chemistry, Karolinska Institutet

1978 - Professor of Chemistry, University of Gothenburg

1979 - Professor of Medical Nutrition and Chairman of the Dept of Medical Nutrition, Huddinge University Hospital, Karolinska Institutet

2006-2008 - Professor of Medical Nutrition and Chairman of the Dept of Biosciences and Nutrition, Karolinska Institutet

2009 - Professor of Medical Nutrition, Karolinska Institute (50%) Robert A. Welch Professor of Dept. of Biology and Biochemistry and Director of Center for Nuclear Receptors and Cell Signaling, University of Houston, Texas (50%)

Administrative Positions

1985 - Director of the Center for Biotechnology, Huddinge University Hospital, Karolinska Institute

1987 - Founder of KaroBio AB (a campus-situated biotechnology company sponsored by pension and governmental funds with about 80 employees).

1979-1991 - Project leader of the Swedish EPA research program on Air Pollution in Urban Areas